In this project we will use genetically engineered mouse models to probe mechanisms of cellular changes that progress to gastric metaplasia and cancer. Mice deficient in Huntingtin interacting protein 1 related (Hip1r) develop a progressive and multifaceted cellular transformation of the stomach. Hip1r is abundant in parietal cells where it is important for vesicular trafficking associated with acid secretion. We have recently determined that Hip1r-deficient mice exhibit glandular hypertrophy, loss of parietal and chief cells, and marked expansion of abnormal mucous neck cells (mucous gland metaplasia). These features are widespread in mice as young as 2 months of age, with dysplasia, metaplasia and eventual antral tumors emerging in older mice (6-8 months). Parietal cell loss results in impaired acid secretion and increased gastrin occurs as a homeostatic response to attempt to normalize acid. We hypothesize that increased gastrin is responsible for increased proliferation of the acid-secreting stomach. This will be tested in AIM 1 by crossing Hip1r-deficient mice to gastrin-deficient mice, to discern the role of this hormone in the remodeling of the gastric mucosa. Our preliminary studies demonstrate that increased proliferation and hypertrophy are gastrin-dependent. Another key feature of the Hip1r-deficent stomach is inflammation. Preliminary data shows widespread immune cell infiltrates and increased interferon gamma as components of the response. We have recently localized interferon gamma receptor expression to the mucous neck cells, thus linking cytokine signaling pathways to the key target cell altered in mucous cell metaplasia. In Aim 2 we will test the hypothesis that interferon gamma and immune cells (B and T cells) induce the cellular transformation by crossing Hip1r-deficient mice to immune-depleted mouse strains. Associated with the transformation events in the acid secreting portion of the stomach is the development of tumors in the antral region. The progression to gastric tumors parallels transformation events in the human, including increased expression and signaling of the morphogens sonic and Indian hedgehog. Aim 3 will characterize hedgehog signaling in Hip1r-deficient mice during the progression to dysplasia using hedgehog reporter mouse strains, and test whether increased hedgehog signaling is contributing to the mucosal transformation with the use of cyclopamine to block signaling in the stomach. In addition, the importance of hedgehog for tumor growth will be tested in culture with cyclopamine. Together these experiments will provide mechanistic insights into the complex cellular changes commonly associated with parietal cell atrophy and low acid secretion in the stomach. PUBLIC HEALTH RELEVANCE: This project focuses on a new mouse strain that exhibits classic cellular changes similar to those observed in the development of human gastric cancer. The goal is to define basic mechanisms of stomach cell transformation and test their role in tumor formation. Thus these studies may provide insights into the process of stomach cancer development in human, which is one of the most prevalent causes of cancer death worldwide.